August 29, 2021Circulation
Heart Failure and a Preserved Ejection Fraction: A Side-by-Side Examination of the PARAGON-HF and EMPEROR-Preserved Trials
Key result
Empagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure by 21% (HR 0.79; 95% CI 0.69-0.90; P<0.001) in patients with an ejection fraction >40%.
Why the study?
Do empagliflozin and sacubitril/valsartan improve outcomes in patients with heart failure and a preserved ejection fraction?
Key Points
- To review and compare the clinical findings of the EMPEROR-Preserved and PARAGON-HF trials in managing heart failure with preserved ejection fraction.
- Comparative analysis of the randomized EMPEROR-Preserved trial evaluating empagliflozin and the PARAGON-HF trial evaluating sacubitril/valsartan in patients with heart failure and an ejection fraction >40%.
- Empagliflozin reduced the composite primary end point of cardiovascular death or heart failure hospitalization by 21% (HR, 0.79 [95% CI, 0.69–0.90]; P<0.001).
- The primary outcome was driven predominantly by a 29% reduction in heart failure hospitalizations, demonstrating a consistent effect across all prespecified subgroups.
Structured PICO
Do empagliflozin and sacubitril/valsartan improve outcomes in patients with heart failure and a preserved ejection fraction?
P
Population
Patients with chronic heart failure and an ejection fraction >40%.
I
Intervention
Empagliflozin (sodium-glucose cotransporter 2 inhibitor) and sacubitril/valsartan
O
Outcome
Composite of cardiovascular death or hospitalization for heart failurecomposite
Main Result
Hazard Ratio: 0.79 (95% CI 0.69–0.9)
p-value: p=<0.001
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“Clinicians do not need to stop and assess LVEF with echocardiography or other imaging before they decide on how to treat heart failure patients with an SGLT2 inhibitor. Clinicians who are busy can now refer less to LVEF than to the patient's phenotype.”
“We encourage you to forget about ejection fraction. We certainly encourage you to forget about an ejection fraction of less than 40% as having special significance. The 40% ejection fraction divide is artificial. It was created in 2003 as part of a trial design, but it has no physiological significance.”
SSScott SolomonCardiologist, Brigham and Women's Hospital
“The findings from PARAGON-HF suggest that some patients with ejection fractions below normal but not at the current definition of HFpEF may benefit from sacubitril-valsartan. It has been previously observed that HFpEF is phenotypically heterogeneous, but I think these data suggest it is therapeutically heterogeneous as well.”
Implication
This commentary highlights the significant 21% reduction in cardiovascular death or HF hospitalization with empagliflozin in HFpEF and compares these landmark findings with the PARAGON-HF trial.
Abstract
Heart failure and a preserved ejection fraction (HFpEF) is characterized in many patients by the coexistence of a systemic metabolic or inflammatory disorder that causes coronary endothelial dysfunction, microvascular rarefaction, and cardiac fibrosis, leading to impaired left ventricular distensibility. Neurohormonal antagonists that are effective in patients with heart failure and a reduced ejection fraction have generally not been useful in patients with HFpEF. Until recently, large-scale trials of patients with HFpEF have reported no benefit or only a modest reduction in the risk of heart failure outcomes, with borderline levels of statistical significance.1,2 The trials have also noted meaningful subgroup interactions, which have further complicated interpretation of the results. The EMPEROR-Preserved (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction) investigators recently reported the effects of the sodium-glucose cotransporter 2 inhibitor empagliflozin in patients with heart failure and an ejection fraction >40%.3 Empagliflozin reduced the risk of the composite of cardiovascular death or hospitalization for heart failure by 21% (hazard ratio, 0.79 [95% CI, 0.69–0.90]; P<0.001), which was related mainly to a 29% decrease in the risk of hospitalization for heart failure. The effect on the primary end point was consistent across all prespecified subgroups. The magnitude of the effect on heart failure hospitalizations with empagliflozin in HFpEF was similar to that previously reported in patients with heart failure and a reduced ejection fraction (29% versus 31% risk reduction, respectively).3,4 Are the results of EMPEROR-Preserved truly different from the results of earlier trials in HFpEF? Two authors of this commentary (M.P. and F.Z.) served on the Executive Committee of both the PARAGON-HF trial (Prospective Comparison of ARNI with ARB Global Outcomes in HF With Preserved Ejection Fraction) with sacubitril/valsartan and the EMPEROR-Preserved trial with empagliflozin; thus, we are well positioned to examine the findings of the 2 landmark HFpEF trials.
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Cite This Study
Packer et al. (2021) conducted an editorial in Heart failure with preserved ejection fraction (HFpEF). Empagliflozin was evaluated on Composite of cardiovascular death or hospitalization for heart failure (HR 0.79, 95% CI 0.69-0.90, p=<0.001). Empagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure by 21% (HR 0.79; 95% CI 0.69-0.90; P<0.001) in patients with an ejection fraction >40%.